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Gustav Smith, MD, PhD

Gustav Smith

Associate professor

Gustav Smith, MD, PhD

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

Author

  • Gustav Smith
  • Janine F. Felix
  • Alanna C. Morrison
  • Andreas Kalogeropoulos
  • Stella Trompet
  • Jemma B. Wilk
  • Olof Gidlöf
  • Xinchen Wang
  • Michael Morley
  • Michael Mendelson
  • Roby Joehanes
  • Symen Ligthart
  • Xiaoyin Shan
  • Joshua C. Bis
  • Ying A. Wang
  • Marketa Sjögren
  • Julius Ngwa
  • Jeffrey Brandimarto
  • David J. Stott
  • David Aguilar
  • Kenneth M. Rice
  • Howard D. Sesso
  • Serkalem Demissie
  • Brendan M. Buckley
  • Kent D. Taylor
  • Ian Ford
  • Chen Yao
  • Chunyu Liu
  • Nona Sotoodehnia
  • Pim van der Harst
  • Bruno H Ch Stricker
  • Stephen B. Kritchevsky
  • Yongmei Liu
  • J. Michael Gaziano
  • Albert Hofman
  • Christine S. Moravec
  • André G. Uitterlinden
  • Manolis Kellis
  • Joyce B. van Meurs
  • Kenneth B. Margulies
  • Abbas Dehghan
  • Daniel Levy
  • Björn Olde
  • Bruce M. Psaty
  • L. Adrienne Cupples
  • J. Wouter Jukema
  • Luc Djousse
  • Oscar H. Franco
  • Eric Boerwinkle
  • Laurie A. Boyer
  • Christopher Newton-Cheh
  • Javed Butler
  • Ramachandran S. Vasan
  • Thomas P. Cappola
  • Nicholas L. Smith
Show all

Summary, in English

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

Department/s

  • Cardiology
  • Heart Failure and Mechanical Support
  • Department of Clinical Sciences, Malmö
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2016-05-01

Language

English

Publication/Series

PLoS Genetics

Volume

12

Issue

5

Document type

Journal article

Publisher

Public Library of Science (PLoS)

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Heart Failure and Mechanical Support

ISBN/ISSN/Other

  • ISSN: 1553-7390